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Alpha-Ketoglutarate: A Novel Therapeutic Strategy to Improve Neurogliovascular Coupling and Cognitive Aging in Older Adults

Award Number: R21AG103782
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Alpha-Ketoglutarate: A Novel Therapeutic Strategy to Improve Neurogliovascular Coupling and Cognitive Aging in Older Adults - PROJECT SUMMARY/ABSTRACT Normal cognitive function requires adequate blood supply to the brain to support neuronal activity. In the healthy young brain, cerebral blood flow is rapidly adjusted to meet the increased oxygen and nutrient demands of active brain regions via a homeostatic mechanism termed neurogliovascular coupling (NGVC). This mechanism involves a complex intercellular signaling network between neuronal, glial, and endothelial cells, which come together to form the neurogliovascular unit (NGVU). Preclinical and clinical studies demonstrate that experimentally induced NGVC dysfunction in young animals results in cognitive impairment and that NGVC is impaired in normal aging and is implicated in the development of age-related cognitive decline. Importantly, restoration of NGVC in aged animals by targeted pharmacological treatments improves NGVC function and cognitive performance. However, there are no clinically approved treatments to reverse age-related NGVC dysfunction in humans. Cellular damage caused by mitochondrial dysfunction and exacerbated oxidative stress, both processes recognized as key hallmarks of brain aging, have been linked to NGVU disruption and subsequent NGVC dysfunction. Yet, to date, very few clinical trials have tested anti-aging interventions for their ability to reduce oxidative stress specifically within NGVU cells, and to assess their effects on NGVC responses and cognition in older adults. Alpha- ketoglutarate (AKG) is an endogenously produced intermediate of the tricarboxylic acid cycle involved in critical cellular metabolism processes, but whose levels decline 10-fold between midlife and older age. This natural decline sparked the interest in using dietary AKG supplementation as an anti-aging intervention supporting cellular antioxidant defenses and mitochondrial function. Early clinical trials indicate AKG is safe and improves frailty outcomes in older adults. However, its potential to reduce oxidative stress within NGVU cells and improve NGVC and cognitive performance in this population remains unknown. Clinically, mitochondrial function and oxidative stress are assessed using circulating or cerebrospinal biomarkers. However, these biomarkers lack specificity for the status of individual NGVU cell types. Emerging evidence supports the use of extracellular vesicles (EVs) as potential biomarkers in age-related neurological impairments. Because EVs carry surface markers specific to their cell of origin, isolating and analyzing EVs from neurons, astrocytes, and vascular cells may provide critical insight into cell-specific contributions to NGVC impairment and associated cognitive decline as well as into cell-specific responses to targeted interventions. This proposal will test the hypothesis that AKG supplementation will improve NGVC responses and cognitive performance in older adults. We will also test the hypothesis that these effects are mediated by a decrease in age- related oxidative stress within NGVU cells. These hypotheses will be tested in a randomized, double-blind, placebo- controlled clinical trial with 24 weeks of AKG supplementation in community dwelling older adults.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $214,500 )
2026	2026	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 560	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	1	8/31/2026	NEW	$214,500
														Subtotal = $214,500

Grand Total All Awards = $214,500

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Alpha-Ketoglutarate: A Novel Therapeutic Strategy to Improve Neurogliovascular Coupling and Cognitive Aging in Older Adults

Award Number: R21AG103782

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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